Enhanced Anti-HIV-1 Antibody Responses in African American Women Seropositive for

描述（由申请人提供）：本提案的总体目标是收集数据，以便开发一种能够预防因药物滥用而有直接或间接感染风险的非洲裔美国妇女感染艾滋病毒-1的疫苗。尽管非洲裔美国女性只占美国女性人口的14%，但在报告的州中，非洲裔美国女性占所有新发艾滋病病例的66%。虽然直接注射吸毒是妇女感染艾滋病毒-1的第二大原因，但多项研究表明，妇女或其伴侣滥用其他形式的药物是异性传播艾滋病毒的近端原因。尽管非裔美国妇女的感染风险不成比例，但很少有针对非裔美国妇女的疫苗开发工作。在本提案中，我们将首先收集该组病毒和抗体反应的数据，这可能有助于开发旨在引发广泛中和抗体（bNAbs）的疫苗。这类信息包括确定在这些受试者中发现的bNAbs识别的新表位。然后，我们将寻求从一组罕见的受试者中恢复HIV包膜基因，这些受试者具有高水平的bNAbs，并且能够在没有抗逆转录病毒治疗（ART）的情况下控制其病毒载量。虽然已经知道能够将病毒载量控制在50至2000拷贝/ml之间并拥有bNAbs（病毒抗体控制器）的患者有一段时间了，但直到最近才发现能够将病毒载量维持在不可检测水平并拥有bNAbs的个体。这些个体具有“精英中和者”（EN）和“精英控制者”（EC）双重表型。初步数据表明，这种表型可能在感染丙型肝炎病毒的非裔美国妇女中比其他危险群体更常见。然后，我们将使用遗传分析，包括祖先重建，来恢复和表征这些受试者中引起bNAb反应的包膜基因。我们将使用这些基因生产重组包膜蛋白（rgp120和gp140），并在小动物免疫原性研究中测试它们作为候选疫苗免疫原。经过超过25年的疫苗研究，迄今为止所描述的艾滋病毒疫苗中没有一种能够持续引发广泛中和的抗体。此外，迄今为止临床开发的所有疫苗免疫原都是在不考虑病毒供体的中和抗体反应的情况下选择的。本提案中的研究将是第一个评估已知在人体中刺激bnab的疫苗免疫原的功效的研究。这些研究也将是首次尝试复制在一组罕见的非洲裔美国妇女身上看到的保护性免疫反应，这些妇女对艾滋病毒产生了有效的抗病毒免疫反应。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to collect data leading to the development of a vaccine able to prevent HIV-1 infection in African American women who are at risk for infection as a direct or indirect consequence of drug abuse. Although they represent only 14% of the female population in the US, African American women make up 66% of all new HIV/AIDS cases among women in reporting states. While direct injection drug use is the second major cause of HIV-1 infections in women, multiple studies have shown that other forms of drug abuse by women, or their partners, are a proximal cause of heterosexual transmission of HIV. Despite their disproportionate risk of infection, few if any vaccine development efforts have focused on African American women. In this proposal, we will first collect data on viruses and antibody responses in this group that could facilitate the development of vaccines designed to elicit broadly neutralizing antibodies (bNAbs). Information of this type includes defining novel epitopes recognized by bNAbs found in these subjects. We will then seek to recover HIV envelope genes from a rare group of subjects who possess high levels of bNAbs and are able to control their viral loads without antiretroviral therapy (ART). While patients able to control viral loads between 50 and 2000 copies/ml and possess bNAbs (viremic controllers) have been known for some time, only recently have individuals able to maintain viral loads at undetectable levels and possess bNAbs been identified. These individuals possess the dual "elite neutralizer" (EN), "elite controller" (EC) phenotype. Preliminary data suggest that this phenotype may be more common in HCV-infected African American women than other risk groups. We will then use genetic analysis, including ancestral reconstruction, to recover and characterize the envelope genes that gave rise to bNAb responses in these subjects. We will use these genes to produce recombinant envelope proteins (rgp120 and gp140) and test these as candidate vaccine immunogens in small animal immunogenicity studies. After more than 25 years of vaccine research, none of the HIV vaccines described to date are able to consistently elicit broadly neutralizing antibodies. Moreover, all of the vaccine immunogens in clinical development to date were selected without regard to the neutralizing antibody response in the virus donor. The studies in this proposal will be the first studies to evaluate the efficacy of vaccine immunogens known to have stimulated bNAbs in humans. These will also be the first studies to attempt to replicate the protective immune response seen in a rare group of African American women who have developed effective antiviral immune responses to HIV.